Summary: While blockade of cannabinoid receptor 1 (CB1) has been shown to attenuate diet-induced obesity (DIO), its relative role in different cell types has not been tested. The current study investigated the role of CB1 in immune vs non-immune cells during DIO by generating radiation-induced bone marrow chimeric mice that expressed functional CB1 in all cells except the immune cells or expressed CB1 only in immune cells. CB1−/− recipient hosts were resistant to DIO, indicating that CB1 in non-immune cells is necessary for induction of DIO. Interestingly, chimeras with CB1−/− in immune cells showed exacerbation in DIO combined with infiltration of bone-marrow-derived macrophages to the brain and visceral adipose tissue, elevated food intake, and increased glucose intolerance. These results demonstrate the opposing role of CB1 in hematopoietic versus non-hematopoietic cells during DIO and suggests that targeting immune CB1 receptors provides a new pathway to ameliorate obesity and related metabolic disorders.
